It is well known, that 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine of the Formula (I)
also known as lamotrigine, is the active ingredient of several pharmaceutical compositions used for the treatment of different diseases of the central nervous system (e.g. epilepsy).
The synthesis of substituted 3,5-diamino-1,2,4-triazine derivatives is known from the literature. In the following publications the general synthesis of substituted derivatives is described—Agr. Res. Serif. 3 188 (1966) and J. Med. Chem. 859 (1972)—according to which benzoyl cyanide is reacted with aminoguanidine in acidic medium and the so obtained adduct is cyclized under basic conditions. According to the process described in the European Patent No. 21121—analogously to the method described above—2,3-dichlorobenzoyl cyanide is reacted with the hydrogencarbonate salt of aminoguanidine in dimethyl sulfoxide as solvent, in the presence of 8 N nitric acid for 7 days. The obtained adduct is cyclized with methanolic potassium-hydroxide solution to the final product in 15% yield—calculated on the starting material. Basically similar process is described in the European Patent No. 142306. The disadvantages of the above processes are the extremely aggressive reaction medium, the long reaction time as well as the very low yield.
The European Patent No. 247842 describes a process in which 8 M solution of sulfuric acid is used instead of 8 N nitric acid in the condensation reaction, and the reaction time is 48 h. The cyclization reaction is carried out in n-propanol at reflux temperature. The yield is 41%. The disadvantages of this process are the low yield and the aggressive reaction medium.
Basically similar process is described in the U.S. Pat. No. 6,111,101, in which the condensation is carried out in a mixture of diluted sulfuric acid and acetonitrile for 60 h, then the cyclization is carried out with 1% aqueous potassium hydroxide solution. The yield is 44%. The crude product is purified by recrystallization from methanol with the help of clarifier. The disadvantages of the process are the aggressive medium, the low yield and the very long reaction time.
The modification of the above process is described in the European Patent No. 963980, in which the cyclization reaction is carried out in n-propanol at reflux temperature. The yield is 60%. The product is purified by recrystallization from n-propano 1. The disadvantages of this process are also the long reaction time and the aggressive reaction medium.
According to the International Patent Application No. WO96120934 an intermediate, which is prepared with great difficulty, is converted into lamotrigine by cyclizing in a photo-chemical reactor in 80% yield. The disadvantage of the process is that it can not be applied on industrial scale.
The International Patent Application No. WO96120935 describes a six-step synthesis, which is difficult to carry out and hardly realizable on industrial scale, as well as the yield of the final product is very low. The disadvantages of the process are the complicated synthesis, the applied hazardous reagents and the low yield.
It is apparent from the above mentioned facts, that according to the known processes the lamotrigine and the intermediate adduct can only be synthesized in low yield using aggressive reagents and long reaction time. Our aim was to elaborate an industrially applicable process, in which simple industrial operations are used and high purity lamotrigine can be synthesized in good yield, economically, applying short reaction times, without using hazardous reagents.